Process for the preparation of 17alpha-monoesters of 11beta,17alpha,21-trihydroxysteroids

ABSTRACT

17A-MONOESTERS OF 11B,17A,21-TRIHYDROXYSTEROIDS ARE PREPARED BY SILYLATING THE 11B-HYDROXYL GROUP OF AN 11B, 17A-DIHYDROXY-21-ACLOXY STEROID TO A SILYLOXY GROUP, ESTERIFYING THE 17A-HYDROXYL GROUP, AND THEN REMOVING THE SILYL GROUP AT THE 11B POSITION AND THE ACYL GROUP AT THE 21 POSITION BY HUDROLYSIS OR ALCOHOLYSIS.

United States Patent 3,557,162 PROCESS FOR THE PREPARATION OF 17 a-MONO- ESTERS 0F 11B,17u,21-TRIHYDROXYSTEROIDS Jan Lens, Voorschoten, andArthur F. Marx, Delft, Netherlands, assignors to KoninklijkeNederlandsche Gist-en Spiritusfabriek N.V., Delft, Netherlands, acorporation of Netherlands No Drawing. Filed Jan. 23, 1969, Ser. No.793,574 Claims priority, application Great Britain, Jan. 23, 1968,3,587/ 68 Int. Cl. C07c 167/28 US. Cl. 260397.45 2 Claims ABSTRACT OFTHE DISCLOSURE 17a-monoesters of 11,8,17a,21 trihydroxysteroids areprepared by silylating the llfl-hydroxyl group of an 116,l7a-dihydroxy-2l-acyloxy steroid to a silyloxy group, esterifying thel7ot-hydroxyl group, and then removing the silyl group at the 115position and the acyl group at the 21 position by hydrolysis oralcoholysis.

This invention relates to a novel process for the preparation of17a-monoesters of 11fi,17a,21-trihydroxysteroids.

It is known that mild esterification of 11fi,l7a,2l-trihydroxysteroidsresults in the formation of 21-monesters, while under more vigorousconditions 116,21-diesters are produced. Even more vigorous conditionsresult in the formation of the 11B,17a,21-triesters of the1l,B,l7oc,2ltrihydroxysteroids. The l7a-monoesters of these steroidscannot be prepared in this manner.

It is also known that the selective hydrolysis of the l13,17u,21-triesters gives rise to difficulties. Under mild hydrolyzingconditions, the 21-ester group is easily removed. If hydrolysis iscarried out more vigorously, the 17a-acyl group will rearrange into a21-acyl group, whereupon it is easily removed. After hydrolysis of the1711- and the 21-acyl groups, the llfl-acyl group is removed only afterthe application of more vigorous conditions.

According to British patent specification 1,097,164, an 116,170;dihydroXy 21 acyloxyste'roid is acylated at the llfl-position to the1lfl-trihalogenoacetoxy-17ahydroxy-Zl-acyloxysteroid, usingtrihalogenoacetic anhydride in pyridine at a temperature of about 20 C.The starting steroid for this procedure, the115,17a-dihydroxy-Zl-acyloxysteroid, can be prepared according toBritish patent specification 1,097,165 by treating an 1173,17a,21-trihydroxysteroid with an acid anhydride or an acid halogenide inthe presence of a tertiary organic base at a temperature of 030 C. for1-24 hours. The 11,8- trihalogenoacetoxy-17u-hydroxy-2l-acyloxysteroidis then acylated at the 17wposition by treating it with a lower alkanoicacid or the anhydride thereof at room temperature, using a strong acidcatalyst. According to that process it is also possible to effect theacylation with an alkanoic acid as an acylating agent at a temperatureof about 80 C. in the presence of trifluoroacetic anhydride. Thellfi-trihalogenoacetyl group is then removed selectively by treating.the 1lfi-trihalogenoacetoxy-l7a,21 diacylsteroid with a salt of an acidwith a pKa between 2.3 and 7.3, in a lower alcohol. The11fl-hydroxy-17a, 2l-diacylsteroid thus obtained is finally convertedinto the 11,8,21-dihydroxy 17a acyloxysteroid, for eXample by hydrolysiswith perchloric acid in methanol at 0 C.

It is also possible to prepare 115,21 dihydroxy-lhacyloxysteroids bypartially using the process according to Dutch patent application6701919. In accordance to Patented Jan. 19, 1971 that patentapplication, 11,8,l7u,2l-trihydroxysteroids can be converted into thecorresponding ZI-methane sulfonates with methane sulfonic acid chloride'in dry pyridine at a temperature of 0 C. The 21-methane sulfonate canthen be converted into the 11;8-nitrate-17ahydroxy-Zl-methane sulfonatesteroid by reaction with acetyl nitrate, whereupon the l7u-hydroxylgroup is acylated with a carboxylic acid anhydride or an acid halogenidein the presence of a strong acid catalyst. According to that process theacylation can also be carried out with a carboxylic acid in the presenceof trifluoro acetic anhydride. The llfi-nitrate group is then reducedselectively, using zinc dust and acetic acid as the reducing agent, thusobtaining the 1LB-hydroxy-17a-acyloxy-21- methane sulfonate steroid.

The llfl-hydroxy 170a acyloxy-Zl-methane sulfonate steroids, which are,according to said patent specification, used as a starting material forthe preparation of llfi-hydroxy 17cc acyloxy-2l-desoxysteroids, can alsobe converted into the 115,21 dihydroxy-17a-acyloxysteroids by mildhydrolysis of the 21-methane sulfonate group.

The above methods for the preparation of 17a-monoesters of115,17a,2l-trihydroxysteroids by selective hydrolysis of11B,17o,21-triesters thereof make it necessary to carry out thehydrolysis of the ester groups at the 11- position and at the21-position respectively, in two different steps.

According to British patent specification 996,080 170:- rnonoesters of11,8,17a,2l-trihydroxysteroids are prepared by reaction of11,6,17a,2l-trihydroxysteroids with an ortho ester in an organicsolvent, in the presence of an acid catalyst. A l'-substituted17a,21-(1-alkoxy)-methylidenedioxysteroid is obtained, which isconverted into the 17a-acyloxy-2l-hydroxysteroid by treatment with anorganic or inorganic acid. However, it turned out that this methodcannot be used for the preparation of 170:- monoesters with an acylgroup which contains more than 9-carbon atoms.

The process according to our invention is characterized by the fact thatthe llji-hydroxyl group of an 11fl,170cdihydroxy-Zl-acyloxysteroid isprotected by converting it into a silyloxy or substituted-silyloxygroup. The 17ahydroxyl group of the llfi-silyloxy orIla-substitutedsilyloxy-17a-hydroXy-2l-acyloxysteroid can then beacylated with the desired acyl group, whereupon the silyl group at thell-position and the acyl group at the 21- position are removed byalcoholysis or hydrolysis under mild conditions. The 2l-monoe-ster canbe obtained by known methods, e.g. by acylation of the 11,8,17a,21-trihydroxy-steroid with an anhydride of a lower alkanoicacid, preferablyacetic acid, in the presence of a tertiary amine, such as pyridine.

A suitable process is disclosed, for example, in the above-mentionedBritish patent specification 1,097,165.

The llfl-silyl ethers are formed by treating the17a-dihydroXy-2l-acryloxysteroid with known silylating agents, forexample halogenosilanes, e.g. trialkylhalogenosilanes, especially lowertrialkylhalogenosilanes such as trimethylchlorosilane,triethylchlorosilane, triethylbromosilane, and the like, silyl aminessuch as hexamethyldisilazane, and the like, silylamides, such astrimethylsilylacetamide and bis-trimethylsilylacetamide, and the like,and other silylating agents well known to those skilled in the art. Thesilylating reaction with a halogenosilane is preferably eifected in thepresence of an HCl-acceptor, e.g. a tertiary amine, such as pyridine,dimethyl aniline, trimethylamine, and the like.

Esterification of the 17et-hYdIOXY group in the 11 3-silyloxy-17a-hydroXy-21-acyloxysteroid can also be carried out by knownmethods employed in the esterification of hydroxyl groups. For example,esterification may be effected with a carboxylic acid anhydride and astrong acid, such as p-toluenesulfonic acid, or with a carboxylic acidand trifluoroacetic anhydride or the like. However, the reaction shouldnot be carried out in the presence of a hydrohalogenic acid. Such anacid may tend to cause cleavage of the silyl ether group. Esterificationmay also be termed acylation.

After esterification or acylation of the l7a-hydroxyl group, theprotecting groups at C and C are subjected to hydrolysis or alcoholysis,preferably under mild conditions to avoid any risk of the l7a-monoesterbeing rearranged to the isomeric 21-monoester. The hydrolysis oralcoholysis is preferably carried out in the presence of water or of alower alkyl alcohol, such as methanol, and a mineral acid, e.g.hydrochloric acid, in accordance with known techniques in this art.Preferably the acylation reaction at the 17a-position and the subsequenthydrolysis are combined. Therefore, the acylation reaction is preferablycontrolled by means of thin layer chromatography. When the reaction hasbeen terminated, hydrolysis or alcoholysis can be carried out by addingwater or a lower alcohol and a strong acid.

The novel method of this invention for the preparation of Hot-monoestersof steroids has two important advantages. It enables the introduction atthe 17a-position of an acyl group derived not only from lower molecularweight carboxylic acids, such as butyric acid, but also from highermolecular weight carboxylic acids, e.g. carboxylic acids containing upto 14 carbon atoms, and above, such as myristic acid, while at the sametime a 17a-monoester can be obtained in two steps starting from an11,8,l711,21-trihydroxysteroid-21-ester. In the method of thisinvention, various 21-monoesters of 11,8,17oc,21- trihydroxysteroids canbe used as starting materials, in particular compounds such as the2l-n1onoesters of hydrocortisone, betamethasone and dexamethasone. Theinvention is, however, not limited to such compounds and the2l-monoesters of various other l1fi,17a,21-trihydroxysteroids may beemployed. Similarly, various ester or acyl groups may form suchmonoesters, although lower acyl groups are preferred. However, theinvention is not limited to monoesters containing any particular 2l-acylgroup and any hydrolyzable acyl group may be used.

The various Not-monoesters of l1B,17a,21-trihydroxysteroids which areobtained as end products of the process of this invention have valuablepharmacological properties, such as extremely potent topicalanti-inflammatory activity. They are suitably used in conventionalmanner applied to other agents of such activity.

The ll-silyl ethers which are produced in the course of carrying outthis invention are novel compounds not heretofore known, and theirprimary utility lies, of course, in their use as intermediates in thepreparation of the end-product 17a-monoesters of 11B,17u,21-trihydroxysteroids.

For a better understanding of the invention, reference will now be madeto the following examples which, however, are given by way ofillustration only:

EXAMPLE I Preparation of dexamethasone 17u-butyrate 15.2 g. of9a-fluoro-11{3,17u,21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione21 acetate (dexamethasone 21-acetate) and 7 ml. of trimethylchlorosilanewere refluxed in 35 ml. of dry pyridine. After three hours, another 7ml. of trimethylchlorosilane were added. The reaction turned out to becomplete after 6 hours. The reaction mixture was then diluted withmethyl isobutyl ketone, and washed successively with dilute sulfuricacid, a sodium bicarbonate solution, and water. After evaporation invacuo, crystalline dexamethasone-1lfi-trimethylsilylether-Zl-acetate wasobtained. The yield was 4.6 g.

I.R. (CHCl 3615, 1745, 1728, 1665, 1628, 1608, 1073 and 840 cm.-

N.M.R. (CDCl 0.25, 0.92 (doublet), 1.02, 1.48, 2.17, 2.94 (multiplet),4.38 (multiplet), 4.93 (doublet), 6.1, 6.34 and 7.07 (AB-structure)p.p.m.

A mixture of 5 g. of dexamethasone llfl-trimethylsilylether 2l-acetate,3.75 ml. of butyric anhydride, 100 mg. of p-toluenesulfonic acid(monohydrate) and 10 ml. of anhydrous benzene was refluxed understirring and exclusion of moisture. Two more portions of 50 mg. ofp-toluenesulfonic acid were added respectively after 2.5 hours and 5.5hours of boiling. The reaction proved to be complete after 7 hours. Thecooled reaction mixture was now diluted with ml. of methanol, whereupon15 ml. of 6 N hydrochloric acid were added. The mixture was left at roomtemperature for 24 hours, whereupon it was neutralized with sodiumacetate and the methanol distilled off in vacuo. The residue wasextracted with methyl isobutyl ketone and the extract evaporated todryness in vacuo. The residue was now dissolved in ben- Zene andchromatographed on silicagel. The matching fractions were combined andevaporated to dryness. The residue was crystallized from amethanol-water mixture. The yield was 0.890 g. of dexamethasone17a-butyrate.

Melting point: 188.5-l90 C., [0c] :+0.5 (c.=1.0; CHCI [a] :+2.6 (c.=1.0;dioxan);

I.R. (CHCl 3610, 3500, 1728, 1708, 1665, 1630, 1608 and 1175 cm.

N.M.R. (CDCI 0.93 (triplet), 0.99 (doublet), 1.04, 1.56, 2.28 (quartet),2.87, 4.30, 6.14, 6.35 and 7.29 (AB- structure) p.p.m.

Calculated for C H O F(462) (percent): C, 67.51; H, 7.63. Found(percent): C, 67.62; H, 7.72.

EXAMPLE II In an analogous way dexamethasone l7a-myristate was prepared.

Melting point: 138142 C., [a] =2 (c.=1.0; CHC1 I.R. (CHCl) 3615, 3500,1729, 1709, 1667, 1630, 1609 and 1175 CIIII'I.

N.M.R. (CDCl 0.90, 1.04, 1.28, 1.59, 2.29 (quartet), 4.30, 6.15, 6.35and 7.28 (AB-structure) p.p.m.

Calculated for C H O F (602) (percent): C, 71.73; H, 9.20. Found(percent): C, 71.59; H, 9.17.

EXAMPLE III Preparation of hydrocortisone 17a-butyrate (A) Preparationof the 11 fi-trimethylsilyl-ether: 1.5 ml. of trimethylchlorosilane wereadded to a solution of 3.4 g. of hydrocortisone 21-acetate in 8 ml. ofpyridine and the mixture was stirred at room temperature for 90 minutes.The reaction mixture was diluted with ml. of methyl isobutyl ketone and16 ml. of 6 N sulfuric acid were added under agitation and cooling. Theorganic layer was separated and washed with dilute sulfuric acid, 10%aqueous sodium bicarbonate and then with water. The solution wasconcentrated in vacuo to a small volume and the crystallizedhydrocortisone 11 6- trimethylsilyl-ether 2l-acetate was collected:yield 4.0 g.; melting point: l95l97 C.;

(c.: 1.0; CHCl Calculated for C H O Si (476.7) (percent): C, 65.51; H,8.46. Found (percent): C, 65.70; H, 8.43.

I.R. (CHCl 3610, 1743, 1724, 1660, 1612, 1060 and 838 cm.-

N.M.R. (CD01 0.15, 0.90, 1.37, 2.16, 3.33, 4.46, 4.805.80 and 5.66p.p.m.

M.S. mol. peak at 476.

(B) Esterification of the 17a-hydroxyl group: To a mixture of 365 ml. ofbutyric anhydride, 10 ml. of anhydrous benzene and 50 mg. ofp-toluenesulfonic acid were added g. of hydrocortisonellfl-trimethylsilylether 21-acetate and the reaction mixture wasrefluxed for 60 to 90 minutes. It was then cooled and diluted with 100ml. of benzene. The solution was washed with aqueous sodium bicarbonateand then with water. The solution obtained was dried on anhydrousmagnesium sulphate and concentrated to dryness in vacuo. The yield was7.0 g. of amorphous hydrocortisone 11,8-trimethylsilylether 17a-butyrate21-acetate.

(C) Solvolysis of hydrocortisone llfi-trimethylsilylether 17a-butyrate21-acetate: To a solution of 7 g. of amorphous hydrocortisone11B-trimethylsilyl-ether 17abutyrate 21-acetate in ml. of methanol wasadded 2 ml. of 6 N hydrochloric acid and the mixture was stirred at roomtemperature for 42 hours. The reaction mixture was then poured into 100ml. of water and the liquids decanted. The insolubles were dissolved inmethylene chloride, the solution washed with water and dried onmagnesium sulphate. The solution was concentrated to dryness in vacuo.The residue was crystallized from ethyl acetate containing a trace ofacetic acid. The yield was 3.1 g. of hydrocortisone 17u-butyratecontaining only a trace of hydrocortisone 2l-butyrate.

Pure hydrocortisone l7ot-butyrate has a melting point of 204-207 C.; [a]=+49 (c.=1.0; CHCl Calculated for C H O (percent): C, 69.42; H, 8.39.Found (percent): C, 69.62; H, 8.38.

IR. (CI-ICl 3612, 3500, 1725, 1665, 1614, 1275 and 1175 cm.-

N.M.R. (CDCl 0.96, 1.47, 3.15 (multiplet), 4.29, 4.5 (multiplet) and 5.7p.p.m.

EXAMPLE IV Preparation of hydrocortisone 17aadamantylcarboxylate Amixture consisting of 1 g. of hydrocortisone 111itrimethylsilyl-ether21-acetate, 1.54 g. of adamantylcar- 'boxylic anhydride, 10 mg. ofp-toluenesulfonic acid in 2 ml. of benzene (anhydrous) was refluxed for7 hours. The reaction mixture was diluted with 20 ml. of benzene andneutralized with NaHCO The crystallized sodium adamantylcarboxylate wasfiltered off and the filtrate was evaporated to dryness in vacuo. Theresidue was dissolved in a mixture consisting of 20 ml. of methanol and1.5 ml. of 6 N hydrochloric acid and boiled for 3 hours. After cooling,the mixture was neutralized with sodium acetate and the steroidprecipitated by addition of water. The precipitate was filtered off,dried and chromatographed on a silicagel-column using a benzeneacetone(10:1) mixture as an eluent.

After combination of the matching fractions and concentration in vacuo,100 mg. of hydrocortisone 17aadamantylcarboxylate were obtained.

Crystallization from heptane gave a product melting between 224-229 C.;[a] =+48.5 (c.=1.0; CHCL LR. (CHCl 3615, 3500, 1715, 1665, 1615 and 1270cm.-

N.M.R. (CDCI 0.94, 1.46, 1.72, 1.86, 4.22, 4.55 and 5.72 p.p.m.

EXAMPLE V Preparation of hydrocortisone 17wmyristate (A) A mixtureconsisting of 3 g. of hydrocortisone 11f!- trimethylsilyl-ether2l-acetate, 5.92 g. of myristic anhydride, mg. of p-toluenesulfonic acidin 6 ml. of benzene (anhydrous) was refluxed for 2 hours. The reactionmixture was diluted with 20 ml. of benzene and washed first with adilute aqueous sodium carbonate solution and then with water. Theextract was evaporated in vacuo to dryness and redissolved in a smallamount of methanol, whereupon sodium myristate crystallized.

The precipitate was filtered off and the filtrate diluted with methanolto 60 ml. To this solution 5 ml. of methylene chloride and 10 ml. of 6 Nhydrochloric acid were added. The reaction mixture was left at roomtemperature for 24 hours and then neutralized with a concentratedaqueous sodium acetate solution.

The organic solvent Was evaporated in vacuo as much as possible and theaqueous residue extracted with methyl isobutyl ketone. The extract wasevaporated to dryness in vacuo and the residue purified on asilicagel-column using a benzene-acetone (10:1) mixture as an eluent.The fractions containing hydrocortisone 17a-myristate were combined andevaporated to dryness. 580 mg. of amorphous chromatographically purehydrocortisone 17amyristate were obtained.

I.R. (CHCl 3620, 3500, 1720, 1663 and 1615 cmr N.M.R. (CDCl 0.88, 0.95,1.26, 1.47, 3.32, 4.3 and 4.5 p.p.m.

Mixed anhydride method (B) A mixture consisting of 1 g. ofhydrocortisone llfltrimethylsilyl-ether 21-acetate, 1.14 g. of myristicacid, 2.5 ml. of trifluoroacetic anhydride in 2 ml. of anhydrousmethylene chloride was stirred at room temperature for 1 hour. Thereaction mixture was diluted with 50 ml. of methylene chloride, washedwith a sodium bicarbonate solution and with water and evaporated todryness in vacuo. The residue was treated with a mixture consisting of50 ml. of methanol, 7.5 ml. of 3 N hydrochloric acid and 10 ml. ofmethylene chloride at room temperature. After 1 hour the mixture wasneutralized with an aqueous sodium acetate solution, concentrated invacuo and the residue extracted with methyl isobutyl ketone.

The extract was evaporated to dryness in vacuo and the residuechromatographed on a silicagel column (elution with a benzene-acetone(20:1) mixture). 470 mg. of hydrocortisone 17a-myristate-21-acetate wereobtained.

Melting point: 122-126 C.; [u] :+59.7 (c.=1.0; CHCl 190 mg. of thediester were added to a mixture of 20 ml. of methanol, 3 ml. of 6 Nhydrochloric acid and 2.5 ml. of methylene chloride and stirred at roomtemperature for 24 hours. After neutralization with an aqueous sodiumacetate solution the organic solvents were evaporated under reducedpressure and the aqueous residue extracted with methyl isobutyl ketone.The extract was evaporated to dryness in vacuo and the residuechromatographically purified as described under A. 160 mg. of amorphousproduct were obtained. This product was, according to its LR. and N.M.R.spectra, identical to the product obtained according to the methoddescribed under A.

EXAMPLE VI Preparation of hydrocortisone 17ot-cyclipropylcarboxylate Amixture of 5 g. of hydrocortisone llfi-trimethylsilylether 21-acetate,50 mg. of p-toluenesulfonic acid monohydrate, 3.5 ml. of cyclopropanecarboxylic acid anhydride and 10 ml. of dry benzene was refluxed underanhydrous conditions. After 1.5 hours the reaction was stopped, thereaction mixture cooled to room temperature and diluted with ml. ofmethanol. After addition of 5 ml. of 6 N hydrochloric acid the reactionmixture was stored at room temperature for 48 hours. Then it wasneutrilized using a solution of 5.5 g. of sodium acetate in 30 ml. ofwater. The mixture obtained was concentrated in vacuo to a volume ofabout 30 ml. and the residue extracted with methyl isobutyl ketone. Theorganic extract was evaporated to dryness in vacuo.

The residue was purified chromatographically on a column containing 500g. of silicagel and using a benzeneacetone (10:1) mixture as an eluent.The matching frac tions were combined and evaporated to dryness invacuo. The crystalline residue was recrystallized from an acetoneheptanemixture. 1.86 g. of pure hydrocortisone 17w cyclopropylcarboxylate wereobtained.

Melting point: 213-215 C.; [a] =+69 (c.=1.0; CHCl I.R. (CHCl 3612, 3500,1718, 1664, 1617 and 1178 cmf N.M.R. (CDCl 0.9, 1.45, 4.25, 4.52 and5.72 p.p.m.

Calculated for C25H34O6 (percent): C, 69.77; H, 7.90. Found (percent):C, 69.67 and 69.62; H, 8.03 and 7.99.

EXAMPLE VII Preparation of hydrocortisone l7u-butyrate To a mixture of3.65 ml. of butyric anhydride, 10 ml. of anhydrous dioxane and 50 mg. ofp-toluenesulfonic acid was added g. of hydrocortisonellfi-trimethylsilylether 21-acetate and the reaction mixture was heatedat approximately 100 C. for 2 hours. It was then cooled and ml. ofmethanol and 3 ml. of 3 N hydrochloric acid were added. The mixture wasstirred at room temperature for about 50 hours, and then 100 m1. ofwater were added. The liquids were decanted and the oily precipitate wascrystallized from ethyl acetate containing a trace of acetic acid. Theyield was 2.7 g. of hydrocortisone 17a-butyrate.

As will be seen from the foregoing examples, the acyl groups introducedat the 170L-pOS1tlOIl may be of various types. For example, they may behydrocarbon groups of a straight, branched, or cyclic, including bridgedring, structure. This structure may be saturated or unsaturated, and maybe substituted.

In general, as previously indicated, the individual reaction steps, e.g.silylation and esterification, are carried out in accordance withconventional techniques in the art, the same being true of thehydrolysis or alcoholysis step. In this connection, reference is made tothe above-noted British and Dutch publications for typicalesterification and hydrolysis or alcoholysis (solvolysis) procedures.Silylation procedures are described, for example, in OrganosiliconCompounds by C. Eaborn (Butterworths Scientific Publications, London,1960), particularly chapter 9. Thus, the acylation or esterification atthe 170:- position is advantageously carried out in a solvent which isinert in the reaction environment. Any solvent of this type may beemployed, such as hydrocarbon solvents, e.g. benzene, ethers, e.g.dioxane, halogenated solvents, and the like. Temperature is not aspecific parameter in the silylation and esterification reactions,sufficient heat being applied, where necessary, to cause the reaction toproceed at a reasonable speed. Ordinarily, temperatures of about 15 C.to about C. are suitable, with the refluxing temperature of theparticular solvent employed being particularly convenient in the case ofthe esterification reaction. The silylation reaction can ordinarily bereadily effected at room temperature. The same is true of the hydrolysisor alcoholysis reaction, which ordinarily requires no application ofheat and in which temperature is not critical.

It is intended, therefore, that the specific disclosures contained inthe foregoing description are to be interpreted as illustrative only andnot as limitative of the invention.

We claim:

1. A process for producing 17a-monoesters of 115,17a,21-trihydroxysteroids which comprises silylating the 11- hydroxyl groupof an 1lfi,17a-dihydroxy-2l-acyloxy steroid to a silyloxy group,esterifying the l7u-hydroxyl group, and then removing the silyl group atthe 11;??- position and the acyl group at the 21-position by hydrolysisor alcoholysis.

2. A process as defined in claim 1, wherein the silylation of thellfl-hydroxyl group is carried out with a trialkylhalogenosilane in thepresence of a tertiary amine.

No references cited.

ELBERT L. ROBERTS, Primary Examiner

